Psoriasis vulgaris, ichthyosis syndrome, keratosis of palm and sole, pustulosis of palm and sole and lichen pilaris are dyskeratosis in a broad sense showing various characteristic skin signs such as erythema, wetting, hypertrophy, keratinization and scale. This disease is an intractable chronic disease and causes a big obstacle to comfortableness of daily life of patients. With regard to its pathological background, it has been believed to be based on disorder of growth and differentiation of both inflammatory cells and skin cells.
Psoriasis vulgaris which is a representative disease of dyskeratosis is not fatal, but it is intractable and is accompanied by prejudice for its appearance and also by mental pain. Therefore, there are many cases where the quality of life (QOL) is deteriorated significantly.
Many therapeutic methods have been applied to the above-mentioned keratosis such as psoriasis vulgaris. There is, however, no radical therapy and symptomatic treatment and care over a long period of time have been performed. As a main therapeutic method, external application of adrenocorticosteroidal agents has been widely adopted achieving an excellent therapeutic effect. However, there is also a strong side effect and induction of skin atrophy and rebound has been considered to be a problem in particular.
In recent years, topical application of vitamin D3 derivatives having a 9,10-secopregnane skeleton has been widely used. As compared with steroids, this topically applicable agent has fewer side effects and has an effect to prolong the term before the recurrence is noted (refer, for example, to Non-Patent Reference 1). It has been believed that the vitamin D3derivative is effective for keratosis including psoriasis vulgaris via a suppressive action on the growth of epidermal cells (refer, for example, to Non-Patent References 2and 3), a promotional action on epidermal cell differentiation (refer, for example, to Non-Patent References 4to 6), a suppressive action on cytokine production and a suppressive action on the activation of T cells (refer, for example, to Non-Patent Reference 7), etc.
With regard to a vitamin D3derivative having a 9,10-secopregnane skeleton, for example, there have been known various derivatives such as (1S,3R,20S)-20-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5Z,7E,10(19)-trien-1,3-diol (generic name: maxacalcitol) (its synthetic method and pharmacological actions are mentioned, for example, in Patent Reference 1and its pharmacological actions are mentioned, for example, in Non-Patent References 8to 10), the compounds mentioned in Patent Reference 2. or Non-Patent Reference 11, etc.
On the other hand, it has been well known that 1α,25(OH)2D3which is an active form of vitamin D increases the level of serum calcium concentration together with the level of serum parathyroid hormone whereby calcium homeostasis is maintained and controlled. The most anxious side effects of vitamin D3derivatives which have been clinically used at present are dry mouth, malaise, torpor, anorexia, vomiting, abdominal pain and muscular weakness as a result of the increase in calcium concentration in serum (hypercalcemia). Accordingly, it is necessary to periodically measure the calcium concentration in blood not only in the case where administration is given to patients suffering from hypercalcemia but also in patients who are not suffering from the disease. There is also a limitation on its dose (refer, for example, to Non-Patent References 12and 13).
Consequently, there has been an earnest desire for a vitamin D3derivative which, as compared with conventional vitamin D3derivatives, has a relatively small amount of influence on the systemic calcium metabolism and is able to specifically relieve the dyskeratosis of epidermal cells, as a therapeutic agent for keratosis such as psoriasis vulgaris.    Patent Reference 1:EP-A 0184112    Patent Reference 2:Japanese Patent 2908566    Patent Reference 3:U.S. Pat. No. 6,296,997    Patent Reference 4:U.S. Pat. No. 5,612,325    Patent Reference 5:USP Application 2004-0019023    Patent Reference 6:JP-A-Hei-10-231284    Non-Patent Reference 1:Kobayashi J., et al., Nishinihon-hihuka, 60, 882(1998)    Non-Patent Reference 2:Kondo S., et al., Arch. Dermatol. Res., 292, 550(2000)    Non-Patent Reference 3:Kobayashi T., et al., J. Eur. Acad. Dermatol. Venereol., 5, 132(1995)    Non-Patent Reference 4:Kragballe K., et al., Arch. Dermatol. Res., 282, 164(1990)    Non-Patent Reference 5:Matunaga T., et al., J. Dermatol., 17, 135(1990)    Non-Patent Reference 6:Takahashi H., et al., J. Dermatol. Sci., 31, 21(2003)    Non-Patent Reference 7:Komine M., et al., Arch. Dermatol. Res., 291, 500(1999)    Non-Patent Reference 8:Chem. Pharm. Bull., 39(12), 3221-3224(1991)    Non-Patent Reference 9:Chem. Pharm. Bull., 40(6), 1494-1499(1992)    Non-Patent Reference 10:Chem. Pharm. Bull., 44(12), 2280-2286(1996)    Non-Patent Reference 11:Steroids, 59, 686(1994)    Non-Patent Reference 12:Mizutani J., Iyaku Journal, 39, 122(2003)    Non-Patent Reference 13:Nakagawa H., Iyaku Journal, 39, 93 (2003)    Non-Patent Reference 14:Bull. Chem. Soc. Jpn., 52(7), 1989-1993(1979)    Non-Patent Reference 15:Chem. Pharm. Bull., 44, 2280 (1996)    Non-Patent Reference 16:Bioorg. Med. Chem. Lett., 2, 1713 (1992)    Non-Patent Reference 17:Tetrahedron Lett., 45, 7837(2004)    Non-Patent Reference 18:J. Chem. Soc., 115, 1207(1919)    Non-Patent Reference 19:J. of Pharmacology and Experimental Therapeutics, 305, 675(2003)    Non-Patent Reference 20:J. Chem. Soc. Perkin Trans. 1, 7, 1951(1990)    Non-Patent Reference 21:Bull. Chem. Soc. Jpn, 67, 293 (1994)    Non-Patent Reference 22:J. Org. Chem., 33, 1839. (1968)    Non-Patent Reference 23:Chem. Pharm. Bull., 34(10), 4410-4413(1986)    Non-Patent Reference 24:J. Nutr. Sci. Vitaminol., 26, 545-556(1980)    Non-Patent Reference 25:J. Org. Chem., 66(23), 7832-7840 (2001)    Non-Patent Reference 26:Tetrahedron, 42(11), 2931-2935 (1986)    Non-Patent Reference 27:Tetrahedron Lett., 33, 41; 6193-6196. (1992)    Non-Patent Reference 28:Synthesis, 134-135. (1983)    Non-Patent Reference 29:J. Org. Chem., 68(1), 27-34. (2003)    Non-Patent Reference 30:Yakugaku Zasshi, 72, 1172. (1952)    Non-Patent Reference 31:J. Med. Chem., 31(2), 428-32 (1988)    Non-Patent Reference 32:J. Chem. Soc., 115, 1207. (1919)    Non-Patent Reference 33:J. Am. Chem. Soc., 80, 4969-4971 (1958)    Non-Patent Reference 34:Tetrahedron., 42, 11, 2931-2935 (1986)    Non-Patent Reference 35:Tetrahedron., 42, 11, 2931-2935 (1986)    Non-Patent Reference 36:Synthesis, 7, 1009-1014(1998)    Non-Patent Reference 37:Tetrahedron Lett., 28(15), 1685-1688(1987)    Non-Patent Reference 38:J. Chem. Soc., 503-506(1946)    Non-Patent Reference 39:Tetrahedron Lett., 2749-2752 (1976)    Non-Patent Reference 40:Archiv der Phamazie, 316, 339-346 (1983)    Non-Patent Reference 41:J. Med. Chem., 11, 138-140(1968)    Non-Patent Reference 42:J. Med. Chem., 43, 1508-1518 (2000)    Non-Patent Reference 43:J. Gen. Chem. USSR (Engl. Transl.), 32, 786-788(1962)    Non-Patent Reference 44:J. Org. Chem., 52, 4798-4800 (1987)    Non-Patent Reference 45:Tetrahedron Lett., 42, 1029-1032 (2001)    Non-Patent Reference 46:J. Am. Chem. Soc., 111, 393-395 (1989)    Non-Patent Reference 47:J. Org. Chem., 68, 1367-1375 (2003)    Non-Patent Reference 48:Tetrahedron Lett., 32, 7663(1991)    Non-Patent Reference 49:J. Med. Chem., 4662-4674(1998)    Non-Patent Reference 50:J. Org. Chem., 51, 3098-3108(1986)